PROJECT SUMMARY/ABSTRACT The proposed SBIR Phase II program seeks to select a first-in-class, peripherally-restricted, and long-acting somatostatin receptor 4 (LA-SSTR4) agonist clinical candidate for development as a novel non-addictive analgesic able to replace opioids for the treatment of moderate-to-severe chronic pain. The program is based on strong scientific evidence showing that activation of peripheral SSTR4 produces broad spectrum analgesic activity and pursues a unique therapeutic strategy. LA-SSTR4 agonists are semi-synthetic biologics created using a proprietary peptide-antibody conjugate (PAC) technology and having the following modular structure: [(peptide)-(spacer)-(linker)]2-[antibody carrier]. The peptide module confers agonist activity at peripheral SSTR4, whereas the antibody carrier provides extended duration of action and peripheral selectivity. These unique features will allow us to achieve a markedly differentiated and superior product profile in terms of efficacy, safety, and convenience compared to short-acting and brain-penetrating small molecule SSTR4 agonists. The extended half-life will enable once-weekly to once-monthly subcutaneous dosing, thereby maximizing convenience, compliance, and efficacy. The lack of penetration in the central nervous system (CNS) will prevent unnecessary and undesired interaction with abundantly expressed SSTR4 in the CNS, eliminating any risk of CNS-mediated SSTR4 adverse effects, thereby maximizing safety. Unlike opioids, SSTR4 agonists do not induce constipation, respiratory depression, dependence, addiction, or abuse. Finally, unlike SSTR2 and SSTR5, SSTR4 expression in the pituitary and pancreas is very low, supporting that selective SSTR4 agonists are unlikely to perturb peripheral endocrine functions. The preceding SBIR Phase I program has already established the feasibility of conjugating a short-acting, potent, and selective peptide SSTR4 agonist to the antibody carrier. The resulting LA-SSTR4 agonist lead series has high agonist potency and selectivity for SSTR4 and has demonstrated antinociceptive activity in an animal pain model. The proposed SBIR Phase II program seeks to: Aim 1: optimize the existing lead series and select a clinical candidate for development, Aim 2: validate and prioritize the indication(s) for clinical development using disease-relevant mouse pain models, and Aim 3: characterize the pharmacokinetics and safety/toxicology profile of the clinical candidate in rat and non-human primates to help design subsequent investigational new drug (IND)-enabling studies. Assuming success with the current proposal, the follow up Phase IIb program will establish good manufacturing practices (GMP) production for the clinical candidate and complete the good laboratory practices (GLP) safety/toxicology studies required for the IND application. IMPACT &